Methamphetamine (METH) use is of major public health concern given its prevalence among individuals who are HIV infected and its association with HIV transmission risk behaviors, particularly high-risk sexual behavior. METH use strongly alters brain dopaminergic function. Dopamine (DA) is the primary neurotransmitter involved in the brain's reward system and is associated with impulsive behavior, hypersexuality, and many aspects of cognitive functioning, all of which contribute to decision-making choices that can impact engagement in risk behaviors. Catechol-O-methyltransferase (COMT) is the enzyme responsible for the majority of DA clearance in the frontal cortex, which, along with its connections to subcortical striatal and limbic areas, constitutes the reward-processing and decision-making substrate of the brain. A putative link has been identified between the COMT Val158Met genetic polymorphism and impaired executive functioning. Recent research also suggests a relationship between COMT Val158Met and impulsive tendencies such as novelty seeking. COMT Val alleles are confer a high rate of dopamine clearance, whereas Met alleles confer a low rate. Because both HIV and METH can damage or disrupt the frontostriatal, DA-utilizing brain areas that subserve decision-making, these conditions may interact with the COMT Val158Met genotype to exacerbate risk-taking. Therefore, we propose to investigate the effects of COMT genotype on executive functioning, preexisting impulsive traits, measurable behaviors indicating impulsivity and novelty seeking, as well as decision-making choices, on HIV risk behaviors among individuals with METH dependence and/or HIV infection. We additionally propose to investigate the role of other dopamine system genes (tyrosine hydroxylase, DOPA decarboxylase, monoamine oxidase A and dopamine receptors D1-4) that may be similarly implicated in functions leading to risky decision-making. We will also explore gene-gene interactions and gene-environment interactions (e.g., genotype interacting with amount of METH exposure) that may contribute to the prediction of propensity to engage in risk behaviors. The proposed project aims to elucidate sources of individual variability in vulnerability to DA-related dysfunction and associated risk-taking. Understanding the biologic, neurobehavioral, and personality determinants of risk-taking in the context of METH and HIV can help to explain individual differences in response to risk-reduction interventions and inform the tailoring of future interventions to improve individual success, with the goal of reducing the current rise in HIV-infection rates. PUBLIC HEALTH RELEVANCE: We will take a multidisciplinary approach to understanding the contribution of genetic, neurocognitive, psychophysiologic, and personality determinants of risky decision-making and their relationship to HIV transmission risk behaviors in the context of HIV infection and METH dependence. Findings will add to the understanding of individual differences in response to risk-reduction interventions and have the potential to inform the tailoring of future interventions.